Departments of Medicine, Epidemiology and Biostatistics, McGill University
2025-02-26
Recent NEJM publication - Transcatheter Aortic-Valve Replacement for Asymptomatic Severe Aortic Stenosis
METHODS At 75 centers in the United States and Canada, we randomly assigned, in a 1:1 ratio, patients with asymptomatic severe aortic stenosis to undergo early transcatheter aortic-valve replacement (TAVR) with transfemoral placement of a balloon-expandable valve or clinical surveillance. The primary end point was a composite of death, stroke, or unplanned hospitalization for cardiovascular causes. Superiority testing was performed in the intention-to-treat population.
CONCLUSIONS Among patients with asymptomatic severe aortic stenosis, a strategy of early TAVR was superior to clinical surveillance in reducing the incidence of death, stroke, or unplanned hospitalization for cardiovascular causes. (Funded by Edwards Lifesciences; EARLY TAVR ClinicalTrials.gov number, NCT03042104
Primary outcome (top left) composite of death, stroke, and unplanned cardiac hospitalization
Trial criticized for being unblinded but evidence to support this criticism has been lacking
Let’s look closer at the results and do some simulations
Approximating cumulative incidence to time to event data to perform Cox model analysis
Simulated HR = 0.53, 95% CI 0.43, 0.66 reasonably close to published HR 0.50, 95% 0.40, 0.63
Kaplan Meier Simulation Landmark Analysis
HR = 0.81 (95% CI 0.61, 1.07) p =0.14, IOW no benefit after 1 year
Decision to seek medical care and the decision for hospitalization both have subjective components. There are 4 possible ways unbindedness could contribute to differences in hospitalizations.
patients in the clinical surveillance group knew they had severe disease, and knew they were not treated or “fixed.” This could increase their anxiety favor their conversion from asymptomatic to symptomatic patients—largely, because they knew they had severe disease and were unfixed.
medical staff also knew these patients were not “fixed” and thereby increasing theirprobability of attributing any symptoms, cardiac or not, to their underlying aortic stenosis
early surgery group knew they were “fixed” and would be less likely to consult for any symptoms cardiac or not
similarly medical staff of the early TAVR patients knowing they were “fixed” would be less likely to attribute any symptoms to heart disease
Importantly, all 4 mechanisms would lead to an over-estimate of TAVR benefit in reducing hospitalizations
Consider two Scenarios
Scenario 1 benefit of decrease hospitalization occurs immediately following randomization, e.g. in the first year, with no longer term benefits
Scenario 2 the benefit is present throughout the follow-up perhaps at a smaller initial rate but remains continuous, or perhaps even increases over time.
Logic says Scenario 1 more likely for unblinding effect
Logic says Scenario 2 is more likely for TAVR effect
Landmark analysis compatible with Scenario 1 and therefore…
Opinion also supported by the lack of benefit for the more objective outcomes of death or stroke.
N.B. Further support comes from prior empirical evidence, see here and here, that lack of blinding exaggerates intervention effect estimates, especially in trials with subjective outcomes.
Recent NEJM publication - Colchicine in Acute Myocardial Infarction
METHODS In this multicenter trial with a 2-by-2 factorial design, we randomly assigned patients who had myocardial infarction to receive either colchicine or placebo and either spironolactone or placebo. The results of the colchicine trial are reported here. The primary efficacy outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization, evaluated in a time-to-event analysis. C-reactive protein was measured at 3 months in a subgroup of patients, and safety was also assessed.
CONCLUSIONS Among patients who had myocardial infarction, treatment with colchicine, when started soon after myocardial infarction and continued for a median of 3 years, did not reduce the incidence of the composite primary outcome (death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemiadriven coronary revascularization). (Funded by the Canadian Institutes of Health Research and others; CLEAR ClinicalTrials.gov number, NCT03048825.)
NEJM CONCLUSIONS Among patients who had myocardial infarction, treatment with colchicine, when started soon after myocardial infarction and continued for a median of 3 years, did not reduce the incidence of the composite primary outcome (death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia driven coronary revascularization).
PI to the press “I was a believer in colchicine, but after CLEAR I decided to stop it in my parent”
Questions
1. Why was he believer? (because of COLCOT?)
2. This belief presumably wasn’t universally shared or the necessary equipoise would not have been present to proceed with the CLEAR trial
Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction
NEJM CONCLUSIONS Among patients with a recent myocardial infarction, colchicine led to a significantly lower risk of ischemic cardiovascular events than placebo.
Do you just ignore the previous RCT of 4700 subjects?
Better might be to combine or borrow information between the studies
CLEAR
COLCOT
COMBINED
Academic half day - journal club